Implications of parental exposure to nitrosodimethylamine in rats: immediate and multigenerational effects on toxicological and reproductive parameters

Abstract

N-nitrosamines are agents with mutagenic/carcinogenic potential which can be present in food, cigarettes, cosmetics, and water. Recently, high levels of this compound have been detected in widely used drugs, which have attracted the attention of Anvisa and regulatory agencies around the world. These compounds are metabolically activated by the cytochrome P450 system, leading to the generation of alkylating agents and reactive oxygen species. Thus, recurrent exposure to N-nitrosamines may increase the risk of cancer occurrence as well as impact reproductive health in several species. Although the carcinogenic potential of N-nitrosamines is well established, few studies have investigated their adverse effects on reproduction, especially at low dosages, those that are still considered acceptable by regulatory agencies. Studies have shown that different types of N-nitrosamines have compromised fertility in rabbits and rodents, through hormonal, sperm and histological changes, and decreased activity of the 17²-HSD enzyme, suggesting that these compounds may act as endocrine disruptors. However, data on the adverse effects resulting from maternal and/or paternal exposure to low doses of nitrosamines and their persistence on a multigenerational scale are insufficient. Thus, this study aims to evaluate the consequences of paternal, maternal and combined (paternal and maternal) exposure to Nitrosodimethylamine (NDMA), one of the most commonly found in the environment, on toxicological and reproductive parameters of male and female rats (F0 generation), and to investigate the reproductive and developmental repercussions of male and female offspring (F1 generation). Male parents (paternal exposure) will be exposed to NDMA (0 and 7.2 ng/kg/day; gavage) from the preconceptional period until mating. Female parents (maternal exposure) will be exposed to the same doses as males in the preconceptional, during mating and gestational/lactational periods. The male and female parents will constitute the following groups: 1) Control (control females X control males); 2) NDMA-maternal (NDMA females X control males); 3) NDMA-paternal (control females X NDMA males); 4) NDMA-maternal/paternal (NDMA females X NDMA males). Males (F0 generation) will be euthanized after the mating period and females after the end of the lactation period for hemato-biochemical, sperm, histological, residue quantification (testis/ovary), hormonal, gene expression of steroidogenic and antioxidant enzymes and of androgen and estrogen receptors. The offspring (F1 generation) will be evaluated for early sexual development, sperm, histological, fertility/behavioral, and hormonal parameters in adulthood. This study may contribute to the re-evaluation of current toxicological limits, which will help guide public health policies. (AU)